Preparation of the endometrium and timing of blastocyst transfer in modified natural cycle frozen-thawed embryo transfers (mNC-FET): a study protocol for a randomised controlled multicentre trial

Abstract

IntroductionDespite the high number of frozen embryo transfer (FET) cycles being conducted (190 000 cycles/year) in Europe, the timing of blastocyst transfer and the use of luteal phase progesterone support in modified natural cycle FET (mNC-FET) in assisted reproductive technologies are controversial. In mNC-FET, the timing of blastocyst warming and transfer is determined according to the time of implantation in a natural cycle, aiming to reach blastocyst endometrial synchronicity. However, the optimal day of blastocyst transfer following ovulation trigger is not determined. In addition, the value of luteal phase support to maintain the endometrium remains uncertain. Thus, there is a need to identify the optimal timing of blastocyst warming and transfer and the effect of luteal phase support in a randomised controlled trial design. The aim of this randomised controlled trial is to investigate if progesterone supplementation from the early luteal phase until gestational age 8 weeks is superior to no progesterone supplementation and to assess if blastocyst warming and transfer 6 days after ovulation trigger is superior to 7 days after ovulation trigger in mNC-FET with live birth rates as the primary outcome.Methods and analysisMulticentre, randomised, controlled, single-blinded trial including 604 normo-ovulatory women aged 18–41 years undergoing mNC-FET with a high-quality blastocyst originating from their first to third in vitro fertilisation/intracytoplasmic sperm injection cycle. Participants are randomised (1:1:1:1) to either luteal phase progesterone or no luteal phase progesterone and to blastocyst warming and transfer on day 6 or 7 after human chorionic gonadotropin trigger. Only single blastocyst transfers will be performed.Ethics and disseminationThe study is approved by the Danish Committee on Health Research Ethics (H-18025839), the Danish Medicines Agency (2018061319) and the Danish Data Protection Agency (VD-2018-381). The results of the study will be publicly disseminated.Trial registration numberThe study is registered in EudraCT (2018-002207-34) and on ClinicalTrials.gov (NCT03795220); Pre-results.

Is there a critical LH level for hCG trigger after the detection of LH surge in modified natural frozen-thawed single blastocyst transfer cycles?

“…They concluded that single LH determination prior to ovulation induction in unstimulated cycle FET does not seem to have added clinical value [ 17 ]. However, Saupstad et al [ 20 ] reported that in a natural cycle the follicle size corresponding to the start of LH rise varies between different patients. Therefore, relying on follicular size only may result in the administration of hCG either too early or too late, consequently adversely affecting endometrial receptivity, thereby resulting in asynchronicity between the endometrium and the transferred blastocyst.…”

The Effect of Freezing Twice during Assisted Reproductive Technology on Perinatal and Neonatal Outcomes

“…Many studies have demonstrated that FET has increased risks in terms of gestational age babies and hypertensive disorders of pregnancy [ 14 – 18 , 40 ]. However, the specific mechanism of these pregnancy complications after FET remains unclear.…”

“…Patients are often concerned about whether FET or OC poses a risk to offspring perinatally or after birth. Regarding FET, there are consistent findings of an increased risk of hypertensive disorders of pregnancy and large for gestational age after FET, but the specific reasons for this are not clear [ 14 – 18 ]. Some studies have suggested that the risks might be relevant to FET, as FET may lead to epigenetic changes [ 19 ].…”

Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review

“…Moreover, a Scandinavian multi-center RCT is currently ongoing to explore the optimum timing for transferring a single frozen-warmed blastocyst in modified-NC, that is, hCG+6 days or hCG+7 days (78). In this study, each group is further assigned to receive LPS or not.…”